21/03/2011 AEROSOL DEPOSITION AND THE ASSESSMENT OF PULMONARY DRUG DELIVERY. Fundamentals of aerosols
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1 AEROSOL DEPOSITION AND THE ASSESSMENT OF PULMONARY DRUG DELIVERY AEROSOL DEPOSITION AND THE ASSESSMENT OF PULMONARY DRUG DELIVERY Steve Newman Scientific Consultant Norfolk, UK Fundamentals of aerosols Mechanisms of aerosol deposition Factors which influence aerosol deposition Assessment of pulmonary drug delivery Lung deposition (radionuclide imaging) Pulmonary bioavailability (pharmacokinetics) AEROSOLS AND PULMONARY DRUG DELIVERY Aerosol deposition in lungs is an essential part of successful pulmonary drug delivery Drugs given by inhalation Locally acting drugs (e.g. bronchodilators, corticosteroids) Systemically acting drugs (e.g. peptides, analgesics) Inhaled drug delivery: aerosol particles and droplets Aerosol defined as: a stable dispersion or suspension of solid particles or liquid droplets in a gaseous medium Both solid and liquid dispersions consist of particles AEROSOLS Adapted from Labiris, N.R. and Dolovich, M.B. (003), Br.J.Clin. Pharmacol., 56, TOBACCO SMOKE CAR EXHAUST PARTICLES BACTERIA DUSTS PHARMACEUTICALS FOG POLLENS Aerosol diameter, μm Relative distribution PARTICLE SIZE DISTRIBUTIONS Adapted from Labiris, N.R. and Dolovich, M.B. (003), Br. J. Clin. Pharmacol., 56, Monodisperse aerosols: all particles in a distribution are the same size Pharmaceutical aerosols almost always heterodisperse (polydisperse) COUNT (NUMBER) Median diameter 1 µm MASS (VOLUME) Median diameter 5 µm AERODYNAMIC PARTICLE SIZE Aerodynamic behavior determined by particle size, density and shape Aerodynamic diameter (D a ): Diameter of a spherical unit density particle with the same settling velocity in air Product of (physical diameter) and ( specific gravity) The following have the same aerodynamic diameter:.5 µm particle with density 1 gm/cm 3 5 µm particle with density 0.5 gm/cm Aerosol diameter, µm Cascade impactors classify aerosol particles according to their aerodynamic diameters 1
2 AERODYNAMIC PARTICLE SIZE DISTRIBUTION (APSD) in size band Percent of mass i MMAD: Mass median aerodynamic diameter: 50 point GSD: Geometric standard deviation: (8 point / 16 point) FPF: Fine particle fraction: of mass below 5 µm FPF Aerodynamic diameter, μm 0 0 ent mass Cumulative perce THREE MAJOR DEPOSITION MECHANISMS (1) Inertial impaction Gravitational sedimentation Brownian diffusion THREE MAJOR DEPOSITION MECHANISMS () 0.1 µm Inertial impaction Proportional to D a Q 1 µm 10 µm Diffusion Sedimentation Impaction Gravitational sedimentation Proportional to D a T Brownian diffusion Proportional to (T/D p ) Aerodynamic diameter = Da Inhaled flow rate = Q Residence time = T Physical diameter = Dp OTHER DEPOSITION PROCESSES Electrostatic attraction Most aerosols carry electrostatic charge Image charges induced on airway walls Probability of deposition depends on D p -1/3 Important electrostatic effects in some inhaler devices Plastic add-on devices used with pmdis Direct interception Turbulence Reynolds number Upper airways and large central airways of lungs FACTORS INFLUENCING DEPOSITION Aerodynamic particle size distribution MMAD, GSD, FPF Inhalation parameters Inhaled flow rate (speed of inhalation) Inhaled volume Breathing frequency Breath holding Mouth breathing versus nose breathing Body posture Lung anatomy and disease state Random variations in airway anatomy Disease induced variations in airway anatomy Bronchoconstriction, airway inflammation, excess mucus DEPOSITION OF DIFFERENT PARTICLE SIZES FOR MOUTH BREATHING From Heyder, J. et.al. (1986), J.Aerosol. Sci., 17, Upper airways Conducting airways Alveolated airways Inhaled volume 1.5 L, Inhaled flow rate 5 L/min Upper airways, nose breathing Aerodynamic diameter, µm
3 AEROSOL TARGETING From Bennett, W. et al. (00), J.Aerosol Med., 15, CHARACTERISTICS OF PHARMACEUTICAL AEROSOLS Upper airways Conducting airways D a 5 to 10 µm Aerosol bolus late in breath Alveolated airways D a 1 to 5 µm Slow deep inhalation Stable aerosols Usually monodisperse Unchanging size Usually tidal breathing Pharmaceutical aerosols Usually heterodisperse May change size Evaporation in nebulizers, pmdis Deaggregation of powders Hygroscopic growth Usually single breaths Slow or fast deep inhalation Dependence on inhaler technique MEASURING PULMONARY DRUG DELIVERY Lung deposition Radionuclide imaging Gamma scintigraphy SPECT (Single photon emission computed tomography) PET (Positron emission tomography) GAMMA SCINTIGRAPHY: PRINCIPLE OF THE GAMMA CAMERA Photomultipliers Processor: X and Y signals NaI crystal Pulmonary bioavailability Pharmacokinetic methods 30 minute urinary excretion Charcoal-block Upper airways Techniques which do not measure pulmonary drug delivery: Particle concentrations in inhaled and exhaled air Drug recovery on a filter at the inhaler mouthpiece Lungs Stomach Photo of gamma camera courtesy of Prof. John Fleming, University of Southampton, UK Lead shielding Collimator GAMMA SCINTIGRAPHY: RADIOLABELING Usually 99m Tc radiolabel Ideal gamma ray energy (10 kev) and half-life (6 h) Physical association between 99m Tc and drug particles No suitable radionuclides of H, C, N, O Radiolabeling methods Established methods for pmdis Product-specific methods for DPIs Nebulizer solutions: radiolabel mixed with formulation d dose of delivered RADIOLABELING VALIDATION DATA FOR GAMMA SCINTIGRAPHY STUDY Mean and SD distribution (n=5) of drug and radiolabel in Andersen cascade impactor From Pitcairn, G. et al. (000), J. Aerosol Med., 1, 97-10, with permission T: Throat; PS: Pre-separator; F: Filter Impactor stage Drug before labeling Drug after labeling Radiolabel T PS F 3
4 GAMMA SCINTIGRAPHY: PARAMETERS MEASURED Dose fractionation Lungs, upper airways, device, exhaled air Percent of dose or mass of drug Corrections for tissue attenuation Regional deposition (distribution) Peripheral / central (P/C) or central / peripheral (C/P) deposition ratios Relative to radioactive inert gas distribution (usually 81m Kr) Various methodologies: standardization desirable ISAM working group on standardization GAMMA SCINTIGRAPHY: STRENGTHS AND WEAKNESSES Strengths Simplest of the radionuclide imaging methods Clear demonstration of drug delivery from two-dimensional images Widely used: industry standard * Weaknesses 3D distribution compressed into D Approximations needed to quantify lung dose Virtually any lung region contains large airways, small airways and alveoli Radiolabeling 99m Tc labeling of drug particles Cannot be used to measure drug clearance Process may change particle size distribution *Smaldone, G.C. (001), J. Aerosol Med., 1, SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY (SPECT) Diagram from Lappin, G. and Temple, S., eds, (006), Radiotracers in Drug Development, pp Photograph courtesy of Professor John Fleming, University of Southampton, UK REGIONAL LUNG DEPOSITION DATA IN SPECT (1) Body crosssection Gamma camera head Gamma camera head Scanning couch Regional deposition pattern can be related better to lung anatomy Can detect differences between products that are missed by gamma scintigraphy Images courtesy of Professor John Fleming, University of Southampton, UK REGIONAL LUNG DEPOSITION DATA IN SPECT () Main bronchi Alveolar sacs SPECT: STRENGTHS AND WEAKNESSES Strengths Better basis for quantification than gamma scintigraphy Accuracy better than + 10 Superior regional lung deposition data Combined with X-ray CT or MRI Deposition per generation Deposition in each shell Deposition in individual airway generations Weaknesses Radiolabeling issues similar to gamma scintigraphy May be challenging to find right balance between conflicting requirements of rapid imaging, high counts and low radiation dose Longer imaging times - choice of radiotracer
5 Detector ring POSITRON EMISSION TOMOGRAPHY (PET) Positron & Electron Photon 511 kev Photon 511 kev Bismuth germanate detectors Strengths PET: STRENGTHS AND WEAKNESSES Radiolabeled drug molecules, e.g. 11 C radiolabel Deposition and short-term clearance can be measured Claimed to have best basis for quantification Superior spatial resolution compared to other methods Imaging with 18 F-labeled fluorodeoxyglucose (FDG) Weaknesses Production of radiolabeled drug analogue is not easy Short half-lives of positron-emitting radionuclides 11 C has 0 min half-life Few drugs contain a fluorine atom Costs of PET scanners and cyclotrons ASSESSMENT OF PULMONARY BIOAVAILABILITY ASSESSMENT OF PULMONARY BIOAVAILABILITY GASTROINTESTINAL TRACT BLOODSTREAM LUNGS URINE Drugs with negligible oral bioavailability Pulmonary bioavailability equals systemic bioavailability Systemic concentrations in first 30 min Indices of relative pulmonary bioavailability Charcoal-block method Pulmonary bioavailability from excreted drug Limitations Applicability depends on pharmacokinetic (PK) behavior of individual drugs Relationship of PK parameters to regional deposition not understood No need to use radiolabel in PK studies 30 MINUTE URINARY EXCRETION OF ALBUTEROL FOLLOWING DIFFERENT INHALATION TECHNIQUES Mean and range of dose data, from Hindle, M. et al. (1993), Thorax, 8, RV: Residual volume FRC: Functional residual capacity BH: Breath hold P < 0.01 P < 0.01 COMPARISON OF LUNG DEPOSITION BY GAMMA SCINTIGRAPHY AND PULMONARY BIOAVAILABILITY BY THE CHARCOAL-BLOCK TECHNIQUE Mean and SD data from Newman, S.P. et al. (1995), Pharm. Res., 1, From RV No inhalation From RV From FRC P < 0.05 P < 0.05 Slow flow Fast flow 10 sec BH No BH 5
6 VARIABILITY OF LUNG DEPOSITION FROM INHALERS From Borgström, L. et al. (006), J. Aerosol Med., 19, Data from 187 deposition measurements in 71 studies Healthy subjects and patients, adults and children Pulmonary bioavailability data included in meta-analysis Interaction between aerosol plume and upper airways 90 Coefficient of Variation, 30 Upper airway deposition high Upper airway deposition low IN VITRO / IN VIVO CORRELATIONS Data from over 30 gamma scintigraphy studies, from Newman, S.P. and Chan, H-K. (008), J. Aerosol. Med. Pulm. Drug Deliv., 1, 77-8 Whole lung deposition, 0 0 Line of identity CFC pmdi HFA pmdi CFC pmdi + add-on DPI Soft mist inhaler 0 0 Mean lung deposition, ex-valve Fine particle fraction, (< 6.8 μm diameter) Respiratory tract morphology Computational fluid dynamics DEPOSITION MODELING Particle transport Deposition mechanisms Hygroscopic effects COMPARISON OF CALCULATED AND MEASURED WHOLE LUNG DEPOSITION FOR SIX INHALERS Percentage ex-actuator dose from Thiel, C.G. (1998), J Aerosol.Med., 11, Suppl.1, 3-5 Calculated Measured Complex anatomical features Aerosol heterodispersity Lung deposition, 30 Whole lung deposition Deposition per generation Deposition patterns at bifurcations Inhaler number PULMONARY DRUG DELIVERY DATA Several well-accepted roles: In vivo proof of concept for new products Comparison of old and new devices or formulations Fundamental understanding of pulmonary drug delivery Bridge between in vitro tests and clinical trials Pulmonary drug delivery data are: More variable than in vitro data More reflective of clinical response Unlikely to replace clinical studies of efficacy and safety CONCLUDING REMARKS (1) Deposition mechanisms: Inertial impaction and gravitational sedimentation Brownian diffusion Electrostatic effects, turbulence Deposition depends on: Aerodynamic particle size distribution Inhalation parameters Lung anatomy and disease state Radionuclide imaging and pharmacokinetic methods both important for assessing pulmonary drug delivery 6
7 CONCLUDING REMARKS () Gamma scintigraphy: Simplest and most widely used imaging method Two-dimensional distributions Radiolabeling issues SPECT imaging: Three-dimensional distributions Regional deposition data related better to lung anatomy Radiolabeling issues PET imaging: Most rigorous method Radiolabeled drug molecules But also the most challenging method Increased future role for in silico assessment of pulmonary drug delivery? 7
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